This research proposal focuses on maturational changes in pituitary function as a possible determinant of growth hormone (GH) release in the developing rat. The factors which regulate GH secretion in immature animals are not understood. In vivo studies have suggested indirectly that there may be maturational changes in pituitary responsiveness to physiologic regulators of GH release. The current proposal examines GH release from cultured pituitary cells of developing rats. Rats will be studied at 5 key developmental stages which coincide with major changes in circulating GH levels: fetus (day 20 of a normal 22 day gestation), postnatal day 2, postnatal day 15, adult male and adult female. The project will determine a) the relative sensitivity of the developing somatotroph to growth hormone-releasing factor (GRF), b) the relative inhibitory effect of somatostatin (SRIF) on basal and stimulated GH release during early development, c) the influence of prostaglandins E1 and E2 (PGE1, PGE2) on GH release during early development and the interaction of these agents with GRF, d) the development of the negative feedback effect of Insulin-like Growth Factors I and II (IGF-I,-II) and Multiplication Stimulating Activity (MSA) on pituitary GH release. Preliminary results indicate marked age-dependency in the effect of GRF and SRIF on GH release from pituitary cell cultures. It is planned to e) determine the relative capacity of the immature pituitary to generate cAMP in response to GRF and f) determine the relative sensitivity of the developing somatotroph to GH secretogogues which increase intracellular cAMP content independent of the GRF receptor. Preliminary results indicate quantitative ontogenic differences in the release of GH by (Bu)2cAMP, suggesting the possibility of maturational changes in somatotroph function distal to cAMP formation. The long term goal is to identify those factors which contribute to the maturation of normal neuroendocrine control of GH secretion in order to understand both the physiologic determinants of GH release in growing animals and the pathophysiology of GH secretory disorders. Maturational changes in pituitary function are of potential importance as a) a possible explanation for developmental changes in plasma Gh levels, b) a concept in neuroendocrine ontogeny, and c) a possible site of dysfunction which may contribute to neurosecretory disorders of GH in childhood.